Imatinib in Chronic Myeloid Leukemia - Five Years Single Center Experience.

Background: Chronic myeloid leukemia (CML) treatment standards was completely converted in last decade. This clonal myeloproliferative disease characterized by the Philadelphia (Ph) chromosome genetic abnormality which arises from the chromosomal translocation t(9;22)(q34;q11). This translocation fuses the genes encoding BCR and ABL, resulting in expression of constitutively active protein tyrosine kinase, BCR-ABL. In the pre-Imatinib era CML therapy was focused on decreasing the myeloid line proliferation. Interpheron alpha, nowadays neglected in CML, allowed approximately 30% of patients to achieve cytogenetic remission but it was accompanied by severe side effects. The only known curative therapy in CML was allogeneic stem cell transplantation (alloSCT) but the procedure was restricted to younger patients. The first of tyrosine kinase inhibitors (TKI) introduction was a milestone in CML therapy. Today we are forced to face Imatinib resistance as an expression of point mutations in kinase domains, the second or even the third line treatment is performed, however Imatinib remains the first line, relatively safe and very effective treatment in CML.

Patients: 60 patients (F/M-30/30, median age-51) with CML Ph+ BCR-ABL+ diagnosed in our center in last five years were involved in the study. All diagnoses were based on hematological findings, conventional cytogenetics and nested PCR. In all cases 100% Ph+ metaphases were find by the diagnose. The b3a2 transcript type was detected in 34 cases, b2a2 in 26. All but four patients are still receiving Imatinib in dose 400 mg per day. Due to some economic disturbances in early TKI era the median period between the diagnosis of CML and the beginning of Imatinib treatment was 154 days. Three patients were transplanted from allogeneic donor due to NCyR after 12 months of treatment. One death case was related neither to CML nor to treatment toxicity.

Definitions: Complete hematologic response (CHR) was defined as white blood cell count in peripheral blood <10x10⁹/L, platelet count <10x10⁹/L, no immature cells in blood, basophils<5% in blood or marrow, spleen non palpable. Cytogenetic response was defined as the percentage of Ph+ metaphases in conventional cytogenetics: complete (CCyR) - no Ph+ metaphases, partial (PCyR) - 1–35%, minor (mCyR) - 36–65% and minor/none (NCyR)≥66%. As for molecular response due to our PCR tools we determined complete molecular response (CMoR) as undetectable BCR-ABL transcript also by nested PCR.

Methods: All patients started Imatinib therapy in dose 400 mg per day. Cytogenetic response was determined by conventional cytogenetics and molecular response by nested polymerase chain reaction (PCR).

Results: The median period of treatment is 23 months (3–60 months). All patients achieved CHR after 3 months of Imatinib therapy. In the group of 8 patients NCyR was confirmed by 12 months of treatment. In 3 cases of this group allogeneic bone marrow transplantation was performed. One patient of those eight died as was previously mentioned and four of them were included into second-line treatment trial (Nilotinib). 52 patients achieved CCyR (still sustained) after 12 months of therapy. In 13 cases of these 52 CMoR was recognized.

Conclusions: The management of CML is constantly changing and developing. TKI are today a group of drugs influencing the point mutations in kinase domain, even the most resistant-T315I. The future of CML treatment seems to rely on the balance between subsequent TKI generations, alloSCT and possible side effects of both therapeutic schedules.